ijwh 7155 optimal management of perimenopausal depression 060810[1][1]

7/31/2019 IJWH 7155 Optimal Management of Perimenopausal Depression 060810[1][1]

1/9

2010 Parry, publisher and licensee Dove Medical Press Ltd. This is an Open Access articlewhich permits unrestricted noncommercial use, provided the original work is properly cited.

International Journal of Womens Health 2010:2 143151

International Journal of Womens Health

R E V I E W

open access to scientifc and medical research

Open Access Full Text Article

143

Dove press

submit your manuscript | www.dovepress.com

Dove press7155

Optimal management of perimenopausaldepression

Barbara L ParryDepartment of Psychiatry, Universityof California, San Diego, USA

Correspondence: BL ParryUniversity of California, San Diego, 9500Gilman Dr, La Jolla, CA 92093-0804, USATel +1 619 543 5592Fax +1 619 543 7519Email [email protected]

Abstract: Only recently has the perimenopause become recognized as a time when womenare at risk or new onset and recurrence o major depression. Untreated depression at this timenot only exacerbates the course o a depressive illness, but also puts women at increased risk

or sleep disorders, cardiovascular disease, diabetes, and osteoporosis. Although antidepres-

sant medication is the mainstay o treatment, adjunctive therapy, especially with estrogenreplacement, may be indicated in re ractory cases, and may speed the onset o antidepressantaction. Many, but not all, studies, report that progesterone antagonizes the bene cial e ects o estrogen. Although some antidepressants improve vasomotor symptoms, in general they are notas e ective as estrogen alone or relieving these symptoms. Estrogen alone, however, does notgenerally result in remission o major depression in most (but not all) studies, but may provide

bene t to some women with less severe symptoms i administered in therapeutic ranges. Theselective serotonin reuptake inhibitors (SSRIs) in addition to estrogen are usually more bene -cial in improving mood than SSRIs or estrogen treatment alone or major depression, whereasthe selective norepinephrine and serotonin reuptake inhibitors do not require the addition o estrogen to exert their antidepressant e ects in menopausal depression. In addition to attentionto general health, hormonal status, and antidepressant treatment, the optimal management o

perimenopausal depression also requires attention to the individual womans psychosocial and spiritual well being.Keywords: menopause, depression, management

IntroductionKraepelin initially described involutional melancholia as a distinct clinical entitycharacterized by late onset, symptoms o ear, despondency, agitation, and hypochon-driacal delusions, which ormed the basis o the nomenclature in the second edition o the Diagnostic and Statistical Manual of Mental Disorders (DSM-II). 1 A subsequentreport discounted a syndrome o depression at menopause, 2 which served as the

basis or the removal o involutional melancholia rom the DSM-III. 3 Subsequentndings rom the Cross-National Epidemiologic Study indicated an increase in new

onset o depressive illness in the perimenopausal years (women aged 4549). Thislater work is consistent with a developing database demonstrating an increased risk o major depressive episodes occurring in association with hormonal changes in the

perimenopausal years.The perimenopausal years re er to the time period when womens menstrual cycles

become irregular, generally between 4549 years. According to the World Health Orga-nization and the Stages o Reproductive Aging Workshop (STRAW), 4 menopause is

Number of times this article has been viewed

This article was published in the following Dove Press journal:International Journal of Womens Health8 June 2010
http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://localhost/var/www/apps/conversion/current/tmp/scratch551/Email%[email protected]://localhost/var/www/apps/conversion/current/tmp/scratch551/Email%[email protected]://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/


2/9

International Journal of Womens Health 2010:2144

Parry Dove press


Dove press

Cohen et al 9 also examined the impact o the menopausaltransition on depressive symptoms in 460 women withoutdepressive histories aged between 36 and 45 years. Duringthree years o ollow-up, the menopausal group, especiallywomen with hot fashes, was twice as likely to experiencesigni cant depressive symptoms as the premenopausal group.Major mood disorders occurred in 9.5% o premenopausaland 16.6% o perimenopausal women. These studies all used rigorous, standardized criteria or making psychiatric diag-noses, and their results lend strong support to the hypothesiso increased vulnerability to an MDE occurring at the timeo the menopausal transition.

Clinical phenomenologyand epidemiologyBased on studies rom menopause clinics (see review 10), themost common symptom or which women seek treatmentat menopause is mood change. Almost hal o these womenare clinically depressed and over a third experience their rstepisode o depression in the perimenopausal period. Two-thirds o women in London and three-quarters o women inSan Diego attending a university or community menopauseclinic met criteria or recurrent MDD when evaluated by a

psychiatric interview. 11 Peri- compared with pre- or post-menopausal women had a signi cant increase in depressionrating scores. Mood and sleep disturbances were the mostcommon symptoms in about 75% o women. Depressiveepisodes also are likely to recur in women with bipolar illness

at menopause,12

and there is an increased number o suicidesin women during this time period (4564 years). 13

SleepSystematic studies examining objective measures o sleep incare ully diagnosed patients in relation to endocrine markerso the menopause are limited, and the ndings inconsistent. 14 Perceptions o sleep quality may di er in depressed, com-

pared with healthy menopausal women, and although womenmay complain o sleep disturbances more than men, theyactually have better sleep quality as documented by objectiverecordings. 15 Depressed menopausal women may also reportincreased severity o hot fashes during sleep, but in skinconductance studies o hot fashes, they actually have ewer and shorter hot fashes that disrupt sleep. Moreover, sleep dis-turbances at menopause are related more to underlying sleepdisorders (such as restless leg syndrome or apnea) or anxietysymptoms than to hot fashes. Hot fashes are more likelyto disrupt sleep in the rst, compared with the second, hal o the night because o the suppressive e ects o rapid eye

de ned as 12 months o amenorrhea ollowing the nal men-strual cycle, the mean age o which is 51 years, when levelso ollicle stimulating hormone (FSH) exceed 40 mIU/mL.The determination o menopausal status generally is made byclinical history rather than laboratory parameters, however,given the variability o individual hormonal levels.

Increased incidence of major depressive disorder at menopauseMany methodologic problems, especially o diagnostic and endocrine heterogeneity, characterize studies o menopausalmood disorders. More rigorous studies, which use standard-ized, interview-based assessments o depression in endocrine-de ned phases o the menopausal transition, support anassociation between major depressive disorder (MDD) and menopause. In one such study rom the National Institute o Mental Health (NIMH), Schmidt et al 5 conducted a longi-tudinal evaluation o the relationship between reproductivestatus and mood in perimenopausal women. The investigatorsused the structured clinical interview or DSM-IV (SCID) 6

or assessment o psychiatric diagnoses, and plasma levelso FSH obtained at 36 month intervals or an average o

ve years, to determine pre-, peri-, or postmenopausal status.For the 24 months surrounding womens nal menses, therisk or onset o depression was 14 times higher than or a31-year pre-menopausal time period. Women who developed a major depressive episode (MDE) during the perimeno-

pause were not distinguished rom those who remained asymptomatic on the basis o symptom pro les, personal or

amily history o depression, duration o the perimenopause,vasomotor symptoms, li e events, medical illness, use o medication, vitamins, minerals, or exercise. The timing o the depression, occurring in the context o recently elevated FSH levels, suggested that an endocrine mechanism related tothe perimenopause (estradiol withdrawal and recent onset o

prolonged hypogonadism) was involved in the pathophysiol-ogy o perimenopausal depression. Other systematic studiesare consistent with these ndings. In an eight-year study,Freeman et al 7 ollowed 231 women without depressivehistories who were about to enter menopause. Using theCenter or Epidemiological Studies o Depression (CES-D) 8 scale, they ound that the probability o a high depressionscore ( 16) was our- old greater during the menopausaltransition than during the premenopausal phase. Enteringmenopause was linked to more than double the risk o beingdiagnosed with a depressive disorder and was associated with within-woman increases in FSH and luteinizing hor-mone (LH), and greater variability o estradiol and FSH.
http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/


3/9


Perimenopausal depressionDove press


Dove press

movement (REM) sleep, which occurs predominantly in thesecond hal o the night, on thermoregulation. 16 Women withchronic insomnia, however, are at higher risk or developingdepression. In subjective reports o sleep, lower estradiol lev-els have been associated with poorer sleep quality, increased hot fashes, and increased anxiety and depressive symptoms.Estrogen treatment may improve sleep independent o itse ect on hot fashes. In the Womens Health Initiative (WHI),increased light exposure was associated with improved sleepand mood in older women. 17

Past historyStudies o past psychiatric histories, including illnessrelated to reproductive endocrine change, in women withmenopausal depression support a depressive diathesis atmenopause. Women who develop psychiatric symptoms inmiddle age are more likely to evidence psychiatric vulner-ability, ie, a previous personal or amily psychiatric history.A past history o depressive disorder occurs in over hal o the women. In a ve-year study o 2,565 women aged 45to 55, 18 prior depression was the variable most predictive o subsequent depression.

Psychiatric symptoms at menopause are also related to previous depression associated with the reproductivecycle, such as premenstrual syndrome (PMS) or depres-sion during pregnancy or the postpartum period. Stewartand Boydell 19 ound that psychologic distress duringmenopause was associated with a past history o PMS,depressive disorders treated with antidepressant medica-tion, oral contraceptive-induced dysphoria, postpartum

blues and MDD, suggesting an increased sensitivity toreproductive hormones in these psychiatrically vulnerablewomen. Freeman et al 20 ound that PMS was a predictor o menopausal symptoms and that women in the meno-

pausal transition were up to three times more likely toreport depressive symptoms than premenopausal women.A history o depression was the strongest predictor o thesechanges. 21 In interviews o 347 women 3555 years o agein the Seattle Midli e Womens Health Study, Woods and Mitchell 22 ound that a history o either premenstrual or

postpartum a ective symptoms distinguished women withconsistently depressed mood.

Evidence supports the contention that the perimenopauseincreases susceptibility to depression, particularly, but notnecessarily, among women with li e-long susceptibility toMDD, including those whose MDEs were induced by repro-ductive endocrine change (eg, during the premenstruum,

pregnancy, or postpartum).

Risks of untreated depressionTo determine the optimal treatment or perimenopausaldepression, clinicians must weigh the risks o untreated depres-sion and the bene ts o treatment. Untreated depression duringthe perimenopause exacerbates heart disease, diabetes, and osteoporosis. 2326 More speci cally, with regard to cardiovascu-lar (CV) disease, a higher prevalence o depressive disorders wasassociated with more severe atherosclerosis; 27 recurrent depres-sive, but not anxiety, disorders were associated with a two- old increase in the risk o carotid atherosclerosis in middle-aged women, however, li etime history o a single depressive episodewas not associated with increased risk o plaque, suggestingthat prevention o recurrent depressive episodes may prevent

urther progression o atherosclerosis; patients with depressivesymptoms have lower health bene ts (lower unctioning) a ter coronary artery bypass surgery; 28 symptoms o depression aresigni cantly related to increased risk o CV events in womensuspected o myocardial ischemia, 29 to death rom CV diseaseand, based on the ndings rom the WHI observational study,to all-cause mortality, even a ter controlling or established CVdisease risk actors. 30 As Eaton reviews, 31 major depressionincreases the risk o rst heart attack (odds ratio [OR] 3.9),stroke (OR 2.7) and diabetes (OR 2.23). In addition to depression

being associated with increased bone loss 3235 and racture, 36 itis also associated with other menopausal symptoms o urinaryincontinence 37 and hot fashes. 38

Contributing endocrinemechanismsTo provide optimal treatment or perimenopausal depres-sion, it is worthwhile to examine the possible contributingendocrine mechanisms. Harlow et al 39 ound that womenwith a history o depression were at increased risk or anearlier perimenopausal transition with higher FSH and LHlevels and lower estradiol (E2) levels. In a study examininghormonal predictors o depression in women in transition tothe menopause, Freeman et al 21 ound that rapidly increasingFSH levels were associated with a decreased likelihood o depressive symptoms, whereas increasing estradiol levelswere associated with more depressive symptoms. In a later study, Freeman et al 7 observed that in women without ahistory o depression who were undergoing the menopausaltransition, increased depression ratings on the Center or Epidemiological Studies o Depression scale (CES-D)were associated with increased levels o FSH and LH and increased variability o estradiol, FSH and LH. Other thanlower morning dehydroepiandrosterone (DHEA) and its


4/9


Parry Dove press


Dove press

sul ated metabolite DHEA-S, Schmidt et al 5,40 did not nd associations between basal plasma hormone levels (FSH,LH, E2, estrone-E1, total-T or ree testosterone-FT, E2/LHratio, cortisol) in women with rst onset o major or minor depression during the perimenopause and matched healthycomparison women. However, women with hot fashes whowere older, regardless o the presence o depression, had signi cantly higher plasma levels o FT, LH, and FSH, and lower E2/LH ratios. 40 Depressed mood was also not related tohormonal measures o urinary estrone glucuronide, FSH, or testosterone in the Seattle Midli e Womens Health study. 41 Increased FSH levels and older age can be associated witha poor response to antidepressant treatment in post- versus

premenopausal women. 42 Earlier age at menopause in womenwith lower educational levels increased their risk o depres-sion, but long-term oral contraceptive use ( 10 years) was

protective against depression. 43 Earlier bilateral oophorec-tomy be ore the onset o menopause is associated with anincreased risk o depressive symptoms. 44

It may be the alteration o sleep-endocrine relationshipsthat is associated with major depression during the meno-

pause transition. Antonijevic et al 45 ound increased nocturnalcortisol and alterations in FSH secretion in relation to slowwave sleep in postmenopausal depressed women compared with postmenopausal controls. It also may be that fuctuat-ing, rather than absolute, hormonal levels are associated withdepressive symptoms, emphasizing the need or prospec-tive studies. For example, Ryan et al 46 in their prospectivestudy o the association between endogenous hormones and depressive symptoms in postmenopausal women ound nosigni cant associations between depressive symptoms and absolute levels o sex hormone-binding globulin, testoster-one, ree androgen index, estradiol, ree estradiol, or FSH,

but did nd that women with a decline in total serum estradiolor, to a lesser extent, large increases in FSH over a two-year

period had up to a three- old increased risk o depressivesymptoms. In Freemans 10-year ollow-up study, 38 within-woman increases in FSH were associated with the onset o depressed mood, which preceded the development o hotfashes, associated with increased FSH levels, decreased inhibin levels, and variability o estradiol levels. A decrease inFSH was correlated with improved scores in verbal memoryin perimenopausal women who responded to estrogen aug-mentation o antidepressant medication. 47 In postmenopausaldepression, improved antidepressant response to SSRIs wasinversely correlated with basal levels o LH. 48 The e ects may

be mediated by altered neurotransmitter, neuroendocrine,circadian rhythm, or EEG alpha/beta unction. 49,50

Thus, no speci c absolute levels o hormonal pro lesthat would guide treatment recommendations consistentlycharacterize women at risk or developing perimenopausaldepression. Rather, it appears to be the fuctuating levels o hormones during the menopausal transition, and perhapstheir e ects on other endocrine, neurotransmitter, or cir-cadian systems, that contribute to womens vulnerability

or the development o depressive symptoms during the perimenopause.

TreatmentThe studies examining the e ects o hormone replacementon mood in menopausal depressed patients vary dependingon the diagnosis (eg, MDD), their menopausal status (includ-ing the presence o hot fashes), the dose and preparation o estrogen and progesterone replacement, and the duration o treatment (see review 51).

In initial studies 52 not con ned to menopausal women,25 g o ethinyl estradiol added to imipramine was superior to 50 g o ethinyl estradiol plus imipramine or imipraminealone in 30 women with primary depression. The higher dos-age o estrogen, although associated with less insomnia, wasalso associated with signi cant side e ects (lethargy, hypo-tension, tremor, depersonalization). These ndings suggestthere may be a therapeutic window or estrogen treatment;i endogenous levels are already high, additional estrogensupplementation may lead to toxic reactions.

In a six-week nonrandomized trial 53 in primarily post-menopausal women ( 60 years) with unipolar depression,72 women who received fuoxetine (20 mg/day) and estro-gen replacement therapy (ERT, primarily Premarin ) had agreater improvement in depression ratings than 286 womenon ERT alone (40% versus 17%, respectively). Fluoxetine-treated patients not on ERT did not show bene t greater than

placebo. Thus, estrogen enhanced the e cacy o fuoxetinetreatment. Ping et al 54 also ound that hormone replacementtherapy (HRT) with 0.625 mg o conjugated estrogen and 5 mg o progesterone combined with 20 mg fuoxetine or two months was more e ective in reducing symptoms thanHRT alone in 123 women with menopausal depression. Ina study o sertraline (50150 mg), 55 women over 60 yearsreceiving ERT (without progesterone) had greater globalimprovement, better quality o li e, less anxiety, and modestimprovements in cognitive unctioning than women receivingsertraline but not ERT.

In contrast, in our laboratory, we ound that although oral(12 mg Estrace ) or transdermal (0.10.2 mg Estraderm )17-beta estradiol enhanced the antidepressant e ects o


5/9




Dove press

fuoxetine (1040 mg) in an eight-week pilot study o womenwith peri- or postmenopausal MDD, 56 in a ollow-up random-ized clinical trial, the combination o antidepressant (AD)

plus estrogen was not superior to AD alone; in act, patientsreceiving AD plus estrogen showed smaller (nonsigni cant)reductions in interview-based depression ratings than those

patients receiving AD alone, 51 a nding supported by other studies. 57 Estrogen treatment alone did not signi cantlyreduce symptoms o MDD. Estrogen treatment, however,may accelerate the antidepressant response as shown byRasgon et al 58 with respect to sertraline.

In an open-label pilot study, Freeman et al 59 ound thatthe SSRI escitalopram alone or eight weeks signi cantlyimproved psychologic, vasomotor, and somatic symptoms.Escitalopram was more e cacious or the treatment o depression than ethinyl estradiol and norethindrone acetatein another study. 60 Soares et al 61 ound that in peri- and post-menopausal women with depressive disorders who ailed toshow remission o depression a ter our weeks o estrogentherapy, derived bene t rom adjunctive treatment or eightweeks with 2060 mg o citalopram.

In re ractory depressed patients, however, estrogen mayenhance the e cacy o antidepressant medication. 62,63 Insmall studies 64,65 in which the investigators examined thee ect o gradually increasing doses o Premarin or placebo

or a month in three premenopausal and eight postmenopausalwomen with re ractory depression, although there was nooverall improvement in depression scores with estrogenor placebo, one bipolar patient whose depression had beentreatment-resistant or two years, developed mania that begannine days a ter estrogen treatment. Another patient showed striking improvement a ter one week o estrogen treatmentand was no longer depressed a ter two weeks, a remissionthat lasted three months. Thus, occasionally patients doappear to have therapeutic responses to estrogen. In womenwith treatment-resistant MDD, estrogen supplementation inreplacement dosages may have important additive e ects toAD medication, to which menopausal women may otherwise

be re ractory. Depending on the dosage in relation to pro-gesterone, estrogen also may induce 66 or stabilize 12,67 rapid mood cycling in some patients.

In chronic depression, some studies suggested that inmenopausal women not on estrogen replacement therapy,e cacy and tolerability were better with tricyclic antide-

pressant (TCA) medication. To achieve the same degreeo e cacy and tolerability with the SSRIs in menopausaldepressed women, estrogen replacement needed to be added,

presumably to downregulate postsynaptic serotonin receptors

( ndings based on the animal literature). Additional work,however, supported this di erential e ect o TCA versusSSRI medication in pre-, but not postmenopausal women. Ina urther analysis o women over 50 years, although hormonereplacement therapy (HRT) enhanced the e ect o SSRIs and

placebo response, venla axine, perhaps because o its dualinhibition o serotonin and norepinephrine receptors, did notdi erentially a ect outcome as a unction o the additiono HRT (see review 68), as did mirtazapine in an open trial. 69 Venla axine alone may improve depressive and vasomotor symptoms in women with perimenopausal depression. 70 Methyltestosterone urther augmented the e ects o venla-

axine, but was associated with a high dropout rate. 71 In anopen trial o the serotonin-norepinephrine reuptake inhibitor duloxetine, Jo e et al 72 ound that 60120 mg reduced symp-toms or depression, vasomotor symptoms, sleep, anxiety and

pain a ter eight weeks o treatment.Other studies suggest that estrogen treatment alone or

combined with progestins may reduce depressive symptomsin MDD. 63,7377 Klaiber et al 73 ound that three months o treat-ment with oral conjugated estrogen 525 mg compared with

placebo signi cantly reduced Hamilton ratings o depressionor severe persistent depressions in pre- and postmenopausal

inpatient women unresponsive to other medications which had been withdrawn or 23 weeks, psychotherapy, or electrocon-vulsive therapy. Treatment, however, resulted in improvement,

but not in remission, o symptoms and was not uni orm withinthe group, with women having less chronic illness respondingmore avorably. A shorter length o illness, but not meno-

pausal status or age, was signi cantly related to the amounto improvement. The depressed women had elevated levelso monoamine oxidase (MAO) activity, which were reduced with estrogen therapy, but not placebo. The magnitude o improvement did not correlate with MAO levels, however. In astudy 78 o postmenopausal hysterectomized women, those whoreceived conjugated equine estrogens 0.625 mg/day or sixmonths had a signi cant decrease in depressive mood symp-toms as measured by the Hamilton Rating Scale compared withwomen who received no treatment. In a randomized, controlled trial o eight weeks treatment with 1 mg/day estradiol patch or

placebo, Morrison et al 79 ound no clinically signi cant anti-depressant e ect o estradiol on mild to moderate depressionin postmenopausal women. Although no signi cant increasein depressive symptoms was ound with use o medroxypro-gesterone 10 mg/day or two weeks, positive a ect decreased slightly when combined with estradiol. However, Cagnacciet al 74 ound that estrogens plus progestins reduced depressionand anxiety in climacteric women and that progestins did not


6/9


Parry Dove press


Dove press

counteract the bene cial e ects o estrogen. In contrast, anearlier cross-sectional study by Palinkas and Barrett-Connor 80 in women 50 years and older living in Cali ornia ound thatwomen using noncontraceptive estrogen had signi cantlyhigher Beck Depression Ratings (score 13) than untreated women o the same age. A ter 60 years, depressive symptomsdecreased. The authors postulated that more symptomaticwomen sought treatment.

Overall, in the studies that demonstrated e cacy, 17-betaestradiol, the most active orm o estrogen to cross the blood-

brain barrier, was used or at least our weeks. Soares et al 76 ound that the transdermal patch o 100 g o 17--estradiolor 12 weeks was e cacious compared with placebo in women

with perimenopausal depressive disorders, and that the anti-depressant e ects, but not necessarily the bene t on somaticsymptoms, was maintained our weeks a ter withdrawal.Estrogen levels, however, did not correlate with clinicalresponse. Some depressed women had a satis actory response,despite low levels o estrogen, raising the question o whether estrogen de ciency is really necessary to elicit a therapeuticresponse. 81 In a small open-label study, Cohen et al 77 ound that a our-week course o transdermal estrogen (100 g/day)

bene ted both peri- and postmenopausal women. In the studiesthat used progesterone replacement in addition to estrogen, the

progesterone tended to decrease the bene cial e ects o estro-gen, and in some but not all patients, exacerbated depressivesymptoms, especially in those women who had had previousepisodes o depression or who developed negative a ect rom

progestin-containing contraceptives.In non-depressed clinical samples, investigators in WHI 82

ailed to nd a signi cant e ect o estrogen plus progestinon depressive symptom scores a ter three years. In the Heartand Estrogen/Progestin Replacement Study (HERS), 83 onlywomen with hot fashes who were assigned to hormonetherapy bene ted by having better mental health and ewer depressive symptoms. Women without hot fashes assigned tohormone therapy had greater declines in physical unctions,energy, and atigue. In a study o 48 nondepressed womenaged 4757 years, 84 estrogen treatment (Premarin) enhanced mood, but women given progesterone (Provera ) showed more negative a ect, unless counteracted by higher dosageso estrogen. In nonclinically depressed women who had pre-viously undergone hysterectomy and bilateral oophorectomy,three months o treatment with ethinyl estradiol versus pla-cebo improved depression, anxiety, irritability, and insomniaas assessed by the Hamilton Depression Rating Scale. Treat-ment with a progestin showed less avorable changes, and the e ects were diminished by three months. 85

For hot fashes, randomized controlled trials o SSRIs,selective norepinephrine reuptake inhibitors (SNRIs), gabap-entin and clonidine did provide evidence o e cacy, althoughthe e ect was less than that with estrogen therapy (seereview 86). Venla axine and paroxetine have been studied more extensively than any o the other antidepressants and are more consistent in e ectively reducing the requencyand severity o hot lashes. Desvenla axine, sertraline,fuoxetine, and citalopram should be considered second- or third-line options. Duloxetine, escitalopram, fuvoxamine,and mirtazapine should be reserved as last-line therapy

or hot fashes. 87 Schmidt et al 75 using 0.05 mg/day o the17-estradiol patch or three weeks reduced depressive symp-toms in perimenopausal women, irrespective o the presenceo hot fashes or the duration o treatment. Treatment o hotfashes with hormone therapy is cost-e ective in the US. 88

Regarding the risks o hormonal therapies, althoughthe WHI initially reported an increased incidence o breastcancer or cardiovascular disease in 45/10,000 women over

ve years, 89 the majority o the women in this study wereolder (6079 years) with higher body mass indices. 90 Morerecent evidence suggests that use o HRT within 10 years o the onset o menopause (between 5059 years) is associated with reduced risk o cardiovascular disease. 91 According tothe North American Menopause Society, it is reasonable touse hormonal therapies to treat menopausal symptoms in theabsence o related risk actors such as cardiovascular diseaseor breast cancer, repeatedly presenting the option o stoppingor reducing the dose. 92 The decision to use HRT should bedone in consultation with the individual womans physician,weighing her particular risks and bene ts.

Regarding alternative treatments, St Johns wort and black cohosh appear to be the most use ul in alleviating mood and anxiety changes (not disorders) during menopause. 93

ConclusionPerimenopausal women in particular are at risk or new onsetand recurrence o MDEs. Women with previous histories o PMS or postpartum depression are at increased risk. Thesymptoms may present with eatures o melancholia, agita-tion, somatic symptoms, or sleep disturbances. The increasein MDEs occurring at this time has been ound to be linked to hormonal changes o the menopausal transition, namelyincreased FSH levels, rather than to social or environmentaltriggers, although changes in valued li estyle actors asso-ciated with, or example, motherhood, amily, ertility, or

physical rigor and attractiveness, may precipitate depressivemood changes in predisposed or vulnerable women. Women


7/9




Dove press

who worry about others are at increased risk or developingclinical depression. Other women may value the new- ound independence that these li estyle changes incur.

Untreated depression may exacerbate heart disease,diabetes, and osteoporosis, as well as contributing to anincreased risk or suicide and to a more debilitating courseo the depression that is more re ractory to intervention.

Estrogen treatment alone may reduce hot lashes and improve sleep, but has not been shown consistently to be e -cacious as monotherapy in MDD. In some women re ractoryto particularly SSRI AD medication, addition o estrogen mayenhance e cacy, reduce response time, and obviate the need

or increasing the AD dose with its attendant side e ects. I awoman cannot tolerate estrogen replacement, then antidepres-sant medication other than an SSRI (eg, a TCA such as nortrip-tyline or desipramine; or an SNRI or dual-receptor reuptakeinhibitor, eg, mirtazapine, venla axine, or duloxetine) should betried. For vasomotor symptoms in women who cannot tolerateestrogen therapy, paroxetine or venla axine are the antidepres-sants which have the most evidence or e cacy and tolerability.Progesterone may increase depressive symptoms in womenwith a previous history o depression. Estrogen or progesteronehormone replacement should be given in consultation with agynecologist or primary care physician who can monitor thedevelopment o any untoward side e ects on the uterus, breast,or cardiovascular system. Many women may opt to have annualendometrial biopsies as an outpatient procedure.

The North American Menopause Society consensusstatement indicates that it is reasonable to use HRT insymptomatic women in the perimenopause and, as recentevidence suggests, up to 10 years a ter menopause, given thatthe bene ts may outweigh the risks. The most active ormo estrogen, 17-beta estradiol, is the most likely to cross the

blood-brain barrier and exerts potential bene cial e ects onmood, sleep, cognitive unction, and vasomotor symptoms.

AcknowledgmentsThis work was supported in part by NIH grant R01 MH59919 and

NIH Clinical Research Center (CRC) grant M01 RR00827.

DisclosureThe author reports no conficts o interest in this work.

References1. American Psychiatric Association. DSM-II: Diagnostic and Statistical

Manual of Mental Disorders . Washington, DC.: American PsychiatricAssociation; 1968.

2. Weissman MM. The myth o involutional melancholia. JAMA .1979;242(8):742744.

3. American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental Disorders . 3rd ed. Washington, DC: AmericanPsychiatric Association; 1980.

4. Soules MR, Sherman S, Parrott E, et al. Stages o ReproductiveAging Workshop (STRAW). J Womens Health Gend Based Med .2001;10(9):843848.

5. Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation o therelationship between reproductive status and mood in perimenopausalwomen. Am J Psychiatry . 2004;161(12):22382244.

6. First MB, Gibbon M, Spitzer RL, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders Research Version . New York, NY: Biometrics Research Department, New York State PsychiatricInstitute; 1995.

7. Freeman EW, Sammel MD, Lin H, Nelson DB. Associations o hormones and menopausal status with depressed mood in women withno history o depression. Arch Gen Psychiatry . 2006;63(4):375382.

8. Roberts RE, Vernon SW. The Center or Epidemiologic StudiesDepression Scale: Its use in a community sample. Am J Psychiatry .1983;140(1):4146.

9. Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk or newonset o depression during the menopausal transition: The Harvard studyo moods and cycles. Arch Gen Psychiatry . 2006;63(4):385390.

10. Ayubi-Moak I, Parry BL. Psychiatric aspects o menopause. In:Kornstein SG, Clayton AH, editors. Womens Mental Health.

A Comprehensive Textbook . 1st ed. New York, NY: Guild ord Press;2002:132143.

11. Tam LW, Stucky V, Hanson RE, Parry BL. Prevalence o depression inmenopause: A pilot study. Arch Women Ment Health . 1999;2(4):175181.

12. Khan AY, Ludvigson LR, Stewart M, Gorman JM. Menopause mani-esting as bipolar symptoms. J Psychiatr Pract . 2007;13(5):339342.

13. Allgulander C. Suicide and mortality patterns in anxiety neurosis and depressive neurosis. Arch Gen Psychiatry . 1994;51(9):708712.

14. Parry BL, Martinez LF, Maurer EL, Lopez AM, Sorenson DL,Meliska CJ. Sleep, rhythms and womens mood. Part II: Menopause.Sleep Med Rev . 2006;10(3):197208.

15. Van den Berg JF, Miedema HM, Tulen JH, Ho man A, Neven AK,Tiemeier H. Sex di erences in subjective and actigraphic sleep mea-sures: A population-based study o elderly persons. Sleep . 2009;32(10):13671375.

16. Parry BL. Sleep disturbances are related to sleep disorders and anxiety

symptoms. Menopause . 2007;4(5):812814. 17. Grandner MA, Kripke DF, Langer RD. Light exposure is related to

social and emotional unctioning and to quality o li e in older women. Psychiatry Res . 2006;143(1):3542.

18. Avis NE, Brambilla D, McKinlay SM, Vass K. A longitudinal analysis o the association between menopause and depression. Results rom the Mas-sachusetts Womens Health Study. Ann Epidemiol . 1994;4(3):214220.

19. Stewart DE, Boydell KM. Psychologic distress during menopause:Associations across the reproductive li e cycle. Int J Psychiatry Med .1993;23(2):157162.

20. Freeman EW, Sammel MD, Rinaudo PJ, Sheng L. Premenstrualsyndrome as a predictor o menopausal symptoms. Obstet Gynecol .2004;103(5 Pt 1):960966.

21. Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L.Hormones and menopausal status as predictors o depression in women

in transition to menopause. Arch Gen Psychiatry . 2004;61(1):6270. 22. Woods NF, Mitchell ES. Patterns o depressed mood in midli e women:Observations rom the Seattle Midli e Womens Health Study. Res Nurs

Health . 1996;19(2):111123. 23. Carney RM, Freedland KE. Treatment-resistant depression and mortality

a ter acute coronary syndrome. Am J Psychiatry . 2009;166(4):410417. 24. Rivelli S, Jiang W. Depression and ischemic heart disease: What have we

learned rom clinical trials? Curr Opin Cardiol . 2007;22(4):286291. 25. Carnethon MR, Biggs ML, Barzilay JI, et al. Longitudinal association

between depressive symptoms and incident type 2 diabetes mellitusin older adults: The cardiovascular health study. Arch Intern Med .2007;167(8):802807.


8/9


Parry Dove press


Dove press

26. Diem SJ, Blackwell TL, Stone KL, et al. Depressive symptomsand rates o bone loss at the hip in older women. J Am Geriatr Soc .2007;55(6):824831.

27. Tiemeier H, van Dijck W, Ho man A, Witteman JC, Stijnen T,Breteler MM. Relationship between atherosclerosis and late-li e depres-sion: The Rotterdam Study. Arch Gen Psychiatry . 2004;61(4):369376.

28. Mallik S, Krumholz HM, Lin ZQ, et al. Patients with depressive symp-toms have lower health status bene ts a ter coronary artery bypasssurgery. Circulation . 2005;111(3):271277.

29. Rutledge T, Reis SE, Olson MB, et al. Depression symptom severityand reported treatment history in the prediction o cardiac risk in womenwith suspected myocardial ischemia: The NHLBI-sponsored WISEstudy. Arch Gen Psychiatry . 2006;63(8):874880.

30. Wassertheil-Smoller S, Shumaker S, Ockene J, et al. Depression and cardiovascular sequelae in postmenopausal women. The WomensHealth Initiative (WHI). Arch Intern Med . 2004;164(3):289298.

31. Eaton WW. Medical and Psychiatric Comorbidity Over the Course of Life. Washington, DC: American Psychiatric Publishing; 2006.

32. Michelson D, Stratakis C, Hill L, et al. Bone mineral density in womenwith depression. N Engl J Med . 1996;335(16):11761181.

33. Schweiger U, Weber B, Deuschle M, Heuser I. Lumbar bone mineraldensity in patients with major depression: Evidence o increased boneloss at ollow-up. Am J Psychiatry . 2000;157(1):118120.

34. Jacka FN, Pasco JA, Henry MJ, et al. Depression and bone mineraldensity in a community sample o perimenopausal women: GeelongOsteoporosis Study. Menopause . 2005;12(1):8891.

35. Altindag O, Altindag A, Asoglu M, Gunes M, Soran N, Deveci Z. Rela-tion o cortisol levels and bone mineral density among premenopausalwomen with major depression. Int J Clin Pract . 2007;61(3):416420.

36. Silverman SL, Shen W, Minshall ME, Xie S, Moses KH. Prevalence o depressive symptoms in postmenopausal women with low bone mineraldensity and/or prevalent vertebral racture: Results rom the MultipleOutcomes o Raloxi ene Evaluation (MORE) study. J Rheumatol .2007;34(1):140144.

37. Moghaddas F, Lid eldt J, Nerbrand C, Jernstrom H, Samsioe G.Prevalence o urinary incontinence in relation to sel -reported depres-sion, intake o serotonergic antidepressants, and hormone therapy inmiddle-aged women: A report rom the Womens Health in the Lund Area study. Menopause . 2005;12(3):318324.

38. Freeman EW, Sammel MD, Lin H. Temporal associations o hot

fashes and depression in the transition to menopause. Menopause .2009;16(4):728734.

39. Harlow BL, Wise LA, Otto MW, Soares CN, Cohen LS. Depressionand its infuence on reproductive endocrine and menstrual cycle mark-ers associated with perimenopause: the Harvard Study o Moods and Cycles. Arch Gen Psychiatry . 2003;60(1):2936.

40. Schmidt PJ, Murphy JH, Haq N, Danaceau MA, St Clair L. Basal plasmahormone levels in depressed perimenopausal women. Psychoneuroen-docrinology . 2002;27(8):907920.

41. Woods NF, Smith-DiJulio K, Percival DB, Tao EY, Mariella A,Mitchell S. Depressed mood during the menopausal transition and early postmenopause: Observations rom the Seattle Midli e WomensHealth Study. Menopause . 2008;15(2):223232.

42. Pae CU, Mandelli L, Kim TS, et a l. E ectiveness o antidepressanttreatments in pre-menopausal versus post-menopausal women: A pilot

study on di erential e ects o sex hormones on antidepressant e ects. Biomed Pharmacother . 2009;63(3):228235. 43. Ryan J, Carriere I, Scali J, Ritchie K, Ancelin ML. Li etime hormonal

actors may predict late-li e depression in women. Int Psychogeriatr .2008;20(6):12031218.

44. Rocca WA, Grossardt BR, Geda YE, et al. Long-term risk o depressiveand anxiety symptoms a ter early bilateral oophorectomy. Menopause .2008;15(6):10501059.

45. Antonijevic IA, Murck H, Frieboes RM, Uhr M, Steiger A. On the roleo menopause or sleep-endocrine alterations associated with major depression. Psychoneuroendocrinology . 2003;28(3):401418.

46. Ryan J, Burger HG, Szoeke C, et al. A prospective study o theassociation between endogenous hormones and depressive symptomsin postmenopausal women. Menopause . 2009;16(3):509517.

47. Morgan ML, Cook IA, Rapkin AJ, Leuchter AF. Estrogen augmentationo antidepressants in perimenopausal depression: A pilot study. J Clin

Psychiatry . 2005;66(6):774780. 48. Zanardi R, Rossini D, Magri L, Malaguti A, Colombo C, Smeraldi E.

Response to SSRIs and role o the hormonal therapy in post-menopausaldepression. Eur Neuropsychopharmacol . 2007;17(67):400405.

49. Saletu B, Brandstatter N, Metka M, et al. Double-blind, placebo- controlled, hormonal, syndromal and EEG mapping studies withtransdermal oestradiol therapy in menopausal depression. Psychophar-macology (Berl) . 1995;122(4):321329.

50. Stahl SM. E ects o estrogen on the central nervous system. J Clin Psychiatry . 2001;62(5):317318.

51. Parry BL, Meliska CJ, Martinez LF, et al. Menopause: Neuroendocrinechanges and hormone replacement therapy. J Am Med Womens Assoc .2004;59(2):135145.

52. Prange AJ, Wilson IC, Alltop LB. Estrogen may well a ect responseto antidepressant. JAMA. 1972;219:143144.

53. Schneider LS, Small GW, Hamilton SH, Bystritsky A, Nemero CB,Meyers BS. Estrogen replacement and response to fuoxetine in amulticenter geriatric depression trial. Fluoxetine Collaborative StudyGroup. Am J Geriatr Psychiatry . 1997;5(2):97106.

54. Liu P, He FF, Bai WP, et al. Menopausal depression: Comparison o hormone replacement therapy and hormone replacement therapy plusfuoxetine. Chin Med J (Engl) . 2004;117(2):189194.

55. Schneider LS, Small GW, Clary CM. Estrogen replacement therapyand antidepressant response to sertraline in older depressed women.

Am J Geriatr Psychiatry . 2001;9(4):393399. 56. Tam LW, Parry BL. Does estrogen enhance the antidepressant e ects

o fuoxetine? J Affect Disord . 2003;77(1):8792. 57. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine e cacy in

menopausal women with and without estrogen replacement. J Affect Disord . 1999;55(1):1117.

58. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response tosertraline in postmenopausal women with major depressive disorder:A pilot study. J Psychiatr Res . 2007;41(34):338343.

59. Freeman MP, Hill R, Brumbach BH. Escitalopram or perimenopausaldepression: An open-label pilot study. J Womens Health (Larchmt) .

2006;15(7):857861. 60. Soares CN, Arsenio H, Jo e H, et al. Escitalopram versus ethinyl

estradiol and norethindrone acetate or symptomatic peri- and post-menopausal women: Impact on depression, vasomotor symptoms, sleep,and quality o li e. Menopause . 2006;13(5):780786.

61. Soares CN, Poitras JR, Prouty J, Alexander AB, Shi ren JL, Cohen LS.E cacy o citalopram as a monotherapy or as an adjunctive treat-ment to estrogen therapy or perimenopausal and postmenopausalwomen with depression and vasomotor symptoms. J Clin Psychiatry .2003;64(4):473479.

62. Stahl SM. Basic psychopharmacology o antidepressants, Part 2:Estrogen as an adjunct to antidepressant treatment. J Clin Psychiatry .1998;59 Suppl 4:1524.

63. Rasgon NL, Altshuler LL, Fairbanks LA, et al. Estrogen replacementtherapy in the treatment o major depressive disorder in perimenopausal

women. J Clin Psychiatry . 2002;63 Suppl 7:4548. 64. Shapira B, Oppenheim G, Zohar J, Segal M, Malach D, Belmaker RH.Lack o e cacy o estrogen supplementation to imipramine in resistant

emale depressives. Biol Psychiatry . 1985;20(5):576579. 65. Zohar J, Shapira B, Oppenheim G, Ayd FJ, Belmaker RH. Addition o

estrogen to imipramine in emale-resistant depressives. Psychophar-macol Bull . 1985;21(3):705706.

66. Oppenheim G. A case o rapid mood cycling with estrogen: Implicationsor therapy. J Clin Psychiatry . 1984;45(1):3435.

67. Chouinard G, Steinberg S, Steiner W. Estrogen-progesterone combina-tion: Another mood stabilizer? Am J Psychiatry . 1987;144(6):826.


9/9


International Journal of Womens Health

Publish your work in this journal

Submit your manuscript here: http://www.dovepress.com/international-journal-of-womens-health-journal

The International Journal o Womens Health is an international, peer-reviewed open-access journal publishing original research, reports,reviews and commentaries on all aspects o womens healthcare includ-ing gynecology, obstetrics, and breast cancer. Subject areas include:Chronic conditions (migraine headaches, arthritis, osteoporosis);

Endocrine and autoimmune syndromes; Sexual and reproductivehealth; Psychological and psychosocial conditions. The manuscriptmanagement system is completely online and includes a very quick and air peer-review system. Visit http://www.dovepress.com/testimonials.php to read real quotes rom published authors.

151



Dove press

Dove press

68. Sloan DM, Kornstein SG. Gender di erences in depression and responseto antidepressant treatment. Psychiatr Clin North Am . 2003;26(3):581594.

69. Jo e H, Groninger H, Soares CN, Nonacs R, Cohen LS. An open trialo mirtazapine in menopausal women with depression unresponsiveto estrogen replacement therapy. J Womens Health Gend Based Med .2001;10(10):9991004.

70. Ladd CO, Newport DJ, Ragan KA, Loughhead A, Stowe ZN. Ven-la axine in the treatment o depressive and vasomotor symptoms inwomen with perimenopausal depression. Depress Anxiety . 2005;22(2):9497.

71. Dias RS, Kerr-Correa F, Moreno RA, et al. E cacy o hormone therapywith and without methyltestosterone augmentation o venla axine inthe treatment o postmenopausal depression: A double-blind controlled

pilot study. Menopause . 2006;13(2):202211. 72. Jo e H, Soares CN, Petrillo LF, et al. Treatment o depression and

menopause-related symptoms with the serotonin-norepinephrine reup-take inhibitor duloxetine. J Clin Psychiatry . 2007;68(6):943950.

73. Klaiber EL, Broverman DM, Vogel W, Kobayashi Y. Estrogen therapyor severe persistent depressions in women. Arch Gen Psychiatry .

1979;36(5):550554. 74. Cagnacci A, Volpe A, Arangino S, et al. Depression and anxiety in

climacteric women: Role o hormone replacement therapy. Menopause .1997;4(4):206211.

75. Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: A preliminary report. Am J Obstet Gynecol . 2000;183(2):414420.

76. Soares CN, Almeida OP, Jo e H, Cohen LS. E cacy o estradiolor the treatment o depressive disorders in perimenopausal women:

A double-blind, randomized, placebo-controlled trial. Arch Gen Psy-chiatry . 2001;58(6):529534.

77. Cohen LS, Soares CN, Poitras JR, Prouty J, Alexander AB, Shi ren JL.Short-term use o estradiol or depression in perimenopausal and

postme nopausa l women: A preliminar y repor t. Am J Psychi atry .2003;160(8):15191522.

78. Carranza-Lira S, Valentino-Figueroa ML. Estrogen therapy or depres-sion in postmenopausal women. Int J Gynaecol Obstet . 1999;65(1):3538.

79. Morrison MF, Kallan MJ, Ten Have T, Katz I, Tweedy K, Battistini M.Lack o e cacy o estradiol or depression in postmenopausal women:

A randomized, controlled trial. Biol Psychiatry . 2004;55(4):406412.

80. Palinkas LA, Barrett-Connor E. Estrogen use and depressive symptomsin postmenopausal women. Obstet Gynecol . 1992;80(1):3036.

81. Soares CN, Jo e H, Cohen LS, Almeida OP. E icacy o 17 beta-estradiol on depression: Is est rogen de ciency really necessary? J Clin Psychiatry . 2002;63(5):451; author reply 451452.

82. Hays J, Ockene JK, Brunner RL, et al. E ects o estrogen plus pro-gestin on health-related quality o li e. N Engl J Med . 2003;348(19):18391854.

83. Hlatky MA, Boothroyd D, Vittingho E, Sharp P, Whooley MA.Quality-o -li e and depressive symptoms in postmenopausal womena ter receiving hormone therapy: Results rom the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA. 2002;287(5):591597.

84. Sherwin BB. The impact o di erent doses o estrogen and progestin onmood and sexual behavior in postmenopausal women. J Clin Endocrinol

Metab . 1991;72(2):336343. 85. Dennerstein L, Burrows GD, Hyman GJ, Sharpe K. Hormone therapy

and a ect. Maturitas . 1979;1(4):247259. 86. Pinkerton JV, Pastore LM. Perspective on menopausa l vasomotor

symptoms, CAM, and the SWAN. Menopause . 2007;14(4):601605. 87. Carroll DG, Kelley KW. Use o antidepressants or management o hot

fashes. Pharmacotherapy . 2009;29(11):13571374. 88. Lekander I, Borgstrom F, Strom O, Zethraeus N, Kanis JA.

Cost-e ectiveness o hormone therapy in the United States. J Womens Health (Larchmt) . 2009;18(10):16691677.

89. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and bene ts o estrogen plus progestin in healthy postmenopausal women: Principalresults rom the Womens Health Initiative randomized controlled trial.

JAMA. 2002;288(3):321333. 90. Turgeon JL, McDonnell DP, Martin KA, Wise PM. Hormone therapy:

Physiological complexity belies therapeutic simplicity. Science .2004;304(5675):12691273.

91. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormonetherapy and risk o cardiovascular disease by age and years sincemenopause. JAMA. 2007;297(13):14651477.

92. Ettinger B, Barrett-Connor E, Hoq LA, Vader JP, Dubois RW. When is itappropriate to prescribe postmenopausal hormone therapy? Menopause .2006;13(3):404410.

93. Geller SE, Studee L. Botanical and dietary supplements or mood and anxiety in menopausal women. Menopause . 2007;14(3 Pt 1):

541549.
http://www.dovepress.com/international-journal-of-womens-health-journalhttp://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/http://www.dovepress.com/international-journal-of-womens-health-journal

ijwh 7155 optimal management of perimenopausal depression 060810[1][1]

Documents